Preparations that enable stable preservation of proteins used as pharmaceuticals are required for the formulation of biopharmaceuticals (Non-Patent Document 1).
Generally, there are two known pathways of protein degradation: the degradation pathway involving physical association of protein molecules, such as formation of soluble multimers or precipitate/insoluble material (Non-Patent Document 2) and the degradation pathway involving chemical modification, such as hydrolysis, deamidation, and methionine oxidation (Non-Patent Document 3). When proteins are developed as pharmaceuticals, decrease in biological activities during storage of proteins in the preparations to be provided should be prevented by suppressing insofar as possible both deterioration pathways. Methods for suppressing the degradation pathways as much as possible include optimization of pH of the solution, and optimization of types and concentrations of buffer, salt, and stabilizer.
Antibodies that can be used as pharmaceuticals include whole antibodies, antibody fragments, minibodies, and modified antibodies (fusion proteins between antibodies and other proteins, and antibody conjugates). In general, IgG antibody preparations are required to contain very high concentrations of IgG. Such preparations are known to be extremely difficult to prepare (Non-Patent Document 5). In addition to pH optimization and optimization of buffer type, various attempts have been made to stabilize antibodies. For example, stabilized high-concentration antibody preparations comprising acidic ingredients have been disclosed in WO 02/096457 (Patent Document 1). In these preparations, MgCl2 or CaCl2 are used as additives for antibody stabilization. Meanwhile, it is known that minibodies and the like have a high tendency to aggregate and have very low stability (Non-Patent Documents 8 and 9). scFv monomers are also known to aggregate very easily, and form dimers at high concentrations (Non-Patent Document 10). Thus, in the development of pharmaceuticals that are solution preparations of such antibodies, a very important objective is to stabilize antibody molecules in the solutions (specifically to suppress their aggregation).
In general, freeze-dried proteins are more stable than proteins in solutions (the aggregation is suppressed). Thus, the antibody preparations described above may be formulated as freeze-dried preparations, if it is difficult to formulate the preparations as solutions (Non-Patent Documents 11, 12, and 13). Sucrose has been reported to be an effective excipient when IgG antibodies are freeze-dried (Non-Patent Document 14).
Meglumine has been used as an X-ray contrast medium (meglumine amidotrizoate), an MRI contrast medium (meglumine gadopentetate), or such. However, there is no report on the protein-stabilizing effect of meglumine.    [Non-Patent Document 1] Nat. Rev. Drug Discov. 2005, 4(4), 298-306    [Non-Patent Document 2] Int. J. Pharm. 2005, 289, 1-30    [Non-Patent Document 3] Int. J. Pharm. 1999, 185, 129-188    [Non-Patent Document 4] J. Pharm. Sci. 2004, 93(6), 1390-1402    [Non-Patent Document 5] Pharmaceutical Research 1994, 11(5), 624-632    [Non-Patent Document 6] Clin. Chem. Lab. Med. 2000, 38(8):759-764    [Non-Patent Document 7] Journal of Immunological Methods, 111 (1988), 17-23    [Non-Patent Document 8] FEBS Letters Volume 360, Issue 3, 1995, 247-250    [Non-Patent Document 9] FEBS Letters, 1995, 441, 458-462    [Non-Patent Document 10] J. Mol. Biol. 2002, 320, 107-127    [Non-Patent Document 11] Pharm Biotechnol, 2002, 13, 109-33    [Non-Patent Document 12] Int. J. Pharm. 2000, 203(1-2), 1-60    [Non-Patent Document 13] Pharm. Res. 1997, 14(8), 969-75    [Non-Patent Document 14] J. Pharm. Sci. 2001, 90(3), 310-21    [Patent Document 1] WO 02/096457